Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities Questions and Answers

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1 Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities Questions and Answers Guidance for Industry and Review Staff DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact (CDER) Elaine Hu Cunningham at ; (CBER) Office of Communication, Outreach and Development at or ; (CDRH) Paul Gadiock at ; or (OC) Kristin Davis at U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) Office of the Commissioner (OC) January 2017 Procedural 15422dft.doc

2 Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities Questions and Answers Guidance for Industry and Review Staff Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration New Hampshire Ave., Hillandale Bldg., 4 th Floor Silver Spring, MD Phone: or ; Fax: druginfo@fda.hhs.gov and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD Phone: or ocod@fda.hhs.gov and/or Office of Communication and Education CDRH-Division of Industry and Consumer Education Center for Devices and Radiological Health Food and Drug Administration New Hampshire Ave., Bldg. 66, Room 4621 Silver Spring, MD Phone: or ; Fax: DICE@fda.hhs.gov and/or Office of Policy Office of the Commissioner Food and Drug Administration New Hampshire Ave., Bldg. 32, Room 4232 Silver Spring, MD Tel: U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) Office of the Commissioner (OC) January 2017 Procedural

3 TABLE OF CONTENTS I. INTRODUCTION... 1 II. BACKGROUND... 2 III. QUESTIONS AND ANSWERS... 3 A. Communication of HCEI by Firms to Payors Regarding Approved Drugs... 3 B. Communications by Firms to Payors Regarding Investigational Drugs and Devices... 15

4 1 Drug and Device Manufacturer Communications With Payors, 2 Formulary Committees, and Similar Entities Questions and 3 Answers Guidance for Industry and Review Staff This draft guidance, when finalized, will represent the current thinking of the Food and Drug 8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 11 for this guidance as listed on the title page I. INTRODUCTION This guidance provides answers to common questions regarding firms 2 communication of health 19 care economic information (HCEI) regarding their prescription drugs 3 to payors, formulary 20 committees, or other similar entities 4 with knowledge and expertise in the area of health care 21 economic analysis (collectively referred to as payors). This guidance also addresses common 22 questions relating to dissemination of information about investigational drugs and devices 5 23 (medical products 6 ) to payors before FDA approval or clearance of such products The questions and answers are grouped in the following categories: 26 1 This guidance has been prepared by the Office of Prescription Drug Promotion in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research, the Center for Devices and Radiological Health, and the Office of the Commissioner at the Food and Drug Administration. 2 The term firms refers to medical product manufacturers, packers, and distributors and their representatives. 3 Each biological product that also meets the definition of drug under the Federal Food, Drug, and Cosmetic Act (FD&C Act) is subject to provisions of the FD&C Act applicable to drugs, except that a biological product licensed under section 351 of the Public Health Service Act (PHS Act) is not required to have an approved new drug application under section 505 of the FD&C Act (21 U.S.C. 355). See section 351(j) of the PHS Act (42 U.S.C. 262(j)). For the purposes of this guidance, the term drugs means human prescription drugs, including those that are licensed as biological products. 4 The terms payors, formulary committees, or other similar entities are discussed in Q.A.2/A.A.2 of this guidance. 5 The term device refers to a medical device intended for human use, including a device that is licensed as a biological product. 6 The term medical products refers to both drugs and devices. 1

5 27 Communication of HCEI to payors regarding approved drugs 28 Communications to payors about investigational drugs and devices (investigational 29 products) This guidance describes FDA s current thinking on these topics In general, FDA s guidance documents do not establish legally enforceable responsibilities. 34 Instead, guidances describe the Agency s current thinking on a topic and should be viewed only 35 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 36 the word should in Agency guidances means that something is suggested or recommended, but 37 not required II. BACKGROUND A number of FDA s statutory and regulatory provisions potentially impact firms 43 communications with payors. 8 This guidance provides FDA s thinking on frequently asked 44 questions regarding such communications in order to provide clarity for firms and payors. 7 As used in this guidance, the term investigational products refers to drugs and devices that are not yet approved/cleared by FDA for any use (but which must be approved/cleared to be legally marketed), including products for which firms have submitted or plan to submit a new drug application (NDA), a biologics license application (BLA) (including an application submitted under the 351(k) pathway), an abbreviated new drug application (ANDA), a premarket approval application (PMA), a 510(k) submission, a de novo submission under section 513(f)(2) of the FD&C Act (21 U.S.C. 360c(f)(2)), or a Humanitarian Device Exemption (HDE) application. 8 For example, section 502(a), as amended by section 114 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) (Public Law ) and section 3037 of the 21st Century Cures Act (Public Law ), includes the following provision regarding communication of HCEI to payors about approved drugs: Health care economic information provided to a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of drugs for coverage or reimbursement, shall not be considered to be false or misleading under this paragraph if the health care economic information relates to an indication approved under section 505 or under section 351(a) of the Public Health Service Act [42 U.S.C. 262(a)] for such drug, is based on competent and reliable scientific evidence, and includes, where applicable, a conspicuous and prominent statement describing any material differences between the health care economic information and the labeling approved for the drug under section 505 or under section 351 of the Public Health Service Act. The requirements set forth in section 505(a) or in subsections (a) and (k) of section 351 of the Public Health Service Act shall not apply to health care economic information provided to such a payor, committee or entity in accordance with this paragraph. Information that is relevant to the substantiation of the health care economic information presented pursuant to this paragraph shall be made available to the Secretary [of Health and Human Services] upon request. For purposes of this paragraph, the term health care economic information means any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug. Such analysis may be comparative to the use of another drug, to another health care intervention, or to no intervention. Such term does not include any analysis that relates only to an indication that is not approved under section 505 or under section 351 of the Public Health Service Act for such drug. 2

6 45 Specifically, section III.A provides FDA s thinking on frequently asked questions regarding 46 communication of HCEI to payors about approved prescription drugs. Payors seek a range of 47 information on effectiveness, safety, and cost-effectiveness of approved prescription drugs, 48 including information from firms, to help support their drug selection, formulary management, 49 and/or coverage and reimbursement decisions on a population basis. Often, this information 50 differs from and can be provided in addition to the information FDA reviews in order to make 51 approval decisions. Because coverage and reimbursement decisions by payors impact a large 52 number of patients, FDA believes it is essential that information provided by firms to payors 53 about their drugs be truthful and non-misleading Section III.B provides FDA s thinking on frequently asked questions regarding communications 56 to payors about investigational products. Payors have also indicated that due in part to their need 57 to, in some situations, plan for and make coverage and reimbursement decisions far in advance 58 of the effective date of such decisions, they are also interested in receiving information from 59 firms about medical products that are still under investigation or review by FDA. For the 60 reasons described above, it is essential that information provided by firms about their 61 investigational products be truthful and non-misleading III. QUESTIONS AND ANSWERS A. Communication of HCEI by Firms to Payors Regarding Approved Drugs Q. A.1. What is HCEI, and how can it be presented? A. A.1. HCEI is defined in section 502(a) of the FD&C Act (21 U.S.C. 352(a)) (section (a)) as any analysis (including the clinical data, inputs, clinical or other 72 assumptions, methods, results, and other components underlying or comprising 73 the analysis) that identifies, measures, or describes the economic consequences, 74 which may be based on the separate or aggregated clinical consequences of the 75 represented health outcomes, of the use of a drug. Such analysis may be 76 comparative to the use of another drug, to another health care intervention, or to 77 no intervention. 9 HCEI pertains to the economic consequences related to the 78 clinical outcomes of treating a disease (or specific aspect of a disease) or of 79 preventing or diagnosing a disease. 10 HCEI may include comparative analyses of 80 the economic consequences of a drug s clinical outcomes to alternative options 81 (including the use of another drug) or to no intervention See section 502(a), as amended by section 114 of the Food and Drug Administration Modernization Act of 1997 and section 3037 of the 21st Century Cures Act. As used in this guidance, the term section 502(a) refers to the part of that section specific to HCEI. 10 Ibid. Section 502(a) further provides that HCEI provided to a payor, formulary committee, or other similar entity (payors) that relates to an approved indication and is based on competent and reliable scientific evidence will not be considered false or misleading. Those terms are discussed in Q.A.2/A.A.2, Q.A.4/A.A.4, and Q.A.5/A.A.5 of this guidance. 3

7 83 HCEI can be presented in a variety of ways that can include, but are not limited 84 to, an evidence dossier, a reprint of a publication from a peer-reviewed journal, a 85 software package comprising a model with user manual, or a budget-impact 86 model Q. A.2. What is the appropriate scope of the audience for the communication of HCEI 89 about approved drugs under section 502(a)? A. A.2. Section 502(a) specifies that HCEI can be provided to a payor, formulary 92 committee, or other similar entity with knowledge and expertise in the area of 93 health care economic analysis, carrying out its responsibilities for the selection of 94 drugs for coverage or reimbursement This audience includes payors, 12 formulary committees 13 (e.g., pharmacy and 97 therapeutics committees), drug information centers, technology assessment 98 panels, pharmacy benefit managers, and other multidisciplinary entities that 99 review scientific and technology assessments to make drug selection, formulary 100 management, and/or coverage and reimbursement decisions on a population basis 101 for health care organizations. 14, Such entities are constituted to consider HCEI (and other types of information) 104 through a deliberative process and should have the appropriate range of 105 knowledge and expertise in the area of health care economic analysis needed to 106 interpret HCEI presented to them to inform their population-based decision- 107 making process. 16,17 Expertise in this area is essential to understand and evaluate 108 health care economic analyses and their limitations This guidance does not apply to dissemination of HCEI to other audiences, such 111 as health care providers who are making individual patient prescribing decisions 11 Ibid. 12 The term payors refers to entities that are responsible for the financing or reimbursement of costs associated with health care services (e.g., third-party payers, health plan sponsors). 13 The term formulary committees refers to multidisciplinary committees that have the responsibility for the selection of drugs and the management of a drug formulary. 14 The term health care organizations may include entities such as integrated health care delivery networks, hospitals, and hospital systems. 15 See page 65 of the House Report on Prescription Drug Use Reauthorization and Drug Regulatory Modernization Act of 1997 (H.R. 1411), H.R. Rep. No The report is available at 16 Ibid. 17 See section 502(a). 4

8 112 or consumers (e.g., dissemination via a public Web site). Dissemination of HCEI 113 to these audiences is not covered by the recommendations of this guidance Q. A.3. How does FDA intend to implement this guidance for HCEI disseminated in 116 accordance with section 502(a)? A. A.3. If a firm disseminates to an appropriate audience HCEI that is the type of 119 information within the scope of section 502(a) (i.e., HCEI that relates to an 120 approved indication and is based on competent and reliable scientific evidence 121 (CARSE), as each of these elements is described in this guidance), FDA does not 122 intend to consider such information false or misleading. HCEI should clearly and 123 prominently present the information discussed in Q.A.7/A.A.7 and Q.A.8/A.A in this section, including study design and methodology, generalizability, 125 limitations, sensitivity analyses, and information relevant to providing a balanced 126 and complete presentation. If HCEI includes material differences from the FDA- 127 approved labeling, it must present a conspicuous and prominent statement 128 describing any material differences between the health care economic information 129 and the labeling approved for the drug, 19 as discussed in Q.A.7/A.A In addition, FDA does not intend to use HCEI disseminated consistent with this 132 guidance as providing evidence of a new intended use Q. A.4. Section 502(a) provides that HCEI shall not be considered false or misleading 135 if, among other things, it relates to an [approved] indication. 20 What types of 136 information does FDA consider to relate to an approved indication? A. A.4. To be considered related to an approved indication, HCEI analyses should relate 139 to the disease or condition, manifestation of the disease or condition, or symptoms 140 associated with the disease or condition in the patient population for which the 141 drug is indicated in the FDA-approved labeling The scope of the audience for HCEI is important because it will ensure that the information is presented only to parties who have established procedures and skills to interpret the methods and limitations of economic studies. [Section 502(a)] is not intended to permit manufacturers to provide such health care economic information to medical practitioners who are making individual prescribing decisions nor is it intended to permit the provision of such information in the context of medical education. See page 65 of H.R. Rep. No See section 502(a). 20 Section 502(a)(2)(B) of the FD&C Act also provides that the term HCEI does not include any analysis that relates only to an indication that is not approved under section 505 or under section 351 of the Public Health Service Act. If an analysis is consistent with the recommendations in Q.A.4/A.A.4, FDA would consider it to be within the scope of HCEI as defined in section 502(a). On the other hand, if an analysis does not relate to an approved indication for a drug, as illustrated by the examples at the end of Q.A.4/A.A.4, FDA would not consider it to be within the scope of HCEI as defined in this section. 5

9 143 The table below provides examples of HCEI analyses that FDA believes could be 144 considered related to an approved indication of a drug, despite incorporating 145 information that does not appear within, and may vary in certain respects from, 146 information presented in the FDA-approved labeling. These examples are for 147 illustrative purposes only and are not intended to be comprehensive or restrictive Examples of HCEI Analyses That Relate to the Approved Indication Example Duration of Treatment Description Where the approved indication for a drug does not limit the duration of use, HCEI analyses may incorporate information about the long-term use of the drug for that indication over a period that is different from that addressed in the studies described in the FDA-approved labeling (e.g., if a drug is approved for a chronic condition with no limitation on its duration of use based on 24-week studies, economic consequences beyond 24 weeks can be modeled). Practice Setting Burden of Illness Dosing Patient Subgroups HCEI analyses may be based on use of the drug for its approved indication in practice settings that differ from the settings of the clinical trials submitted to FDA in the application (e.g., results of clinical trials conducted in a fee-for-service setting could be extrapolated to a managed care or other setting). HCEI analyses may be derived from studies of broad management of a disease for which the drug is indicated, including economic consequences of treatment on clinical outcomes (e.g., economic consequences of absent work days as a result of signs and symptoms associated with a disease). HCEI analyses may be based on data or studies of approved dosage forms and strengths of a drug for its approved indication, where the dosing regimen varies from the FDA-approved labeling (e.g., an observational study based on drug utilization data from a health plan database, where actual patient use of an approved dosage form and strength of a drug for an approved indication falls outside the recommended dosing regimen in the label, such as by taking at a different frequency or a different total dose than recommended). HCEI analyses may be derived from analyses of treatment effects in patient subgroups (e.g., demographics, disease severity, co-morbidities) that are 6

10 Example Contains Nonbinding Recommendations Description within the patient population for the approved indication, even if these subgroup analyses were not pre-specified in the studies that formed the basis for approval of the drug. Length of Hospital Stay Validated Surrogate Endpoints Clinical Outcome Assessments (COAs) 23 or Other Health Outcome Measures (e.g., Quality- Adjusted Life Year (QALY)) 24 HCEI analyses may be derived from studies of treatment impacts on length of hospital stay. HCEI analyses may be derived from clinical data demonstrating an effect on a surrogate endpoint that is known to predict clinical benefit (i.e., a validated surrogate endpoint). 21 For example, blood pressure reduction is a validated surrogate endpoint for reduction in certain cardiovascular events (e.g., stroke, myocardial infarction) pertaining to antihypertensive drugs (e.g., calcium channel blockers, angiotensin converting enzyme inhibitors). 22 HCEI analyses may be derived from studies involving the approved indication of a drug that assess COAs (e.g., patient-reported outcomes (PROs), such as compliance/adherence, work productivity, basic activities of daily living) or other health outcome measures (e.g., QALY) when they are evaluated using valid and reliable measures (as determined by experts who are familiar with evaluating the merits of a particular COA or other health outcome measure). 21 See FDA s guidance for industry Expedited Programs for Serious Conditions Drugs and Biologics. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA guidance Web page at If there is insufficient evidence to demonstrate that a particular surrogate endpoint is capable of predicting clinical benefit, it generally should not be used as a basis for HCEI. 22 See FDA s guidance for industry Labeling for Outcome Claims for Drugs to Treat Hypertension. 23 A COA is any assessment of a patient s clinical state by the patient or a clinician. There are four types of COA measures (i.e., patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, and performance outcomes). See FDA s guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 24 A QALY is a measure of the value of a health outcome that is typically scored on a scale from zero (corresponds to death) to one (corresponds to perfect or optimal health), integrating the life expectancy and treatment impact on morbidity of the compared interventions that may be used in HCEI. 7

11 Example Persistence 25 Comparisons Contains Nonbinding Recommendations Description HCEI analyses may be based on data estimating patient persistence on a drug for its approved indication (e.g., estimates based on drug utilization data from a health plan database). HCEI analyses may be derived from studies comparing the safety or effectiveness of a drug for its approved indication to another drug or intervention or to no treatment The following are examples of HCEI analyses that are not considered to relate to 152 an approved indication: An economic analysis of disease course modification related to use of a 155 drug that is approved only to treat the symptoms of the disease would not 156 be considered related to the approved indication. 26 Thus, for example, if 157 an analysis for a drug indicated for the acute relief of angina discussed the 158 effect of the drug on delaying the worsening of coronary artery disease 159 (disease course modification), FDA would not consider this to relate to the 160 approved indication. Similarly, an analysis based on prolonging patient 161 survival (disease course modification) for patients with heart failure would 162 not be considered related to an indication for a drug approved only for the 163 treatment of the signs and symptoms of heart failure. 27 As illustrated by 164 these examples, if a drug is approved only to relieve the symptoms of a 165 disease, HCEI analyses regarding use of the drug to prevent, cure, or 166 mitigate/change the course of the disease would not be considered related 167 to the drug s approved indication HCEI analyses derived from studies in patient populations that are not 170 within the indicated patient population are not related to the approved 171 indication of the drug. For example, an analysis regarding the treatment of 172 cystic fibrosis (CF) in patients with any mutation in the CF gene would 173 not be considered to relate to the approved indication for a drug approved 174 to treat only one specific CF gene mutation The term persistence refers to the duration of time from initiation to discontinuation of therapy. See Cramer JA, Roy A, Burrell A, et al., Medication Compliance and Persistence: Terminology and Definitions, Value Health, 2008;11(1): See page 66 of H.R. Rep. No Ibid. 8

12 176 Q. A.5. What evidentiary support should firms have for their HCEI under section (a)? A. A.5. Section 502(a) states that HCEI shall not be considered false or misleading if, 180 among other things, it is based on competent and reliable scientific evidence. 181 FDA considers HCEI to be based on CARSE if the HCEI has been developed 182 using generally-accepted scientific standards, appropriate for the information 183 being conveyed, that yield accurate and reliable results. In evaluating whether the 184 amount and type of evidence that forms the basis for a particular communication 185 of HCEI meets the generally-accepted scientific standards for such information, 186 FDA will consider the merits of existing current good research practices for 187 substantiation developed by authoritative bodies (e.g., International Society for 188 Pharmacoeconomic and Outcomes Research (ISPOR), Patient-Centered 189 Outcomes Research Institute). For example, when evaluating HCEI based on 190 indirect treatment comparisons in the absence of data from head-to-head 191 controlled clinical trials, FDA may refer to guidelines issued by external expert 192 bodies regarding current rigorous methodologies and best practices for such 193 comparisons (e.g., network meta-analyses) HCEI should clearly and prominently present the information discussed in 196 Q.A.7/A.A.7 and Q.A.8/A.A.8 of this guidance, including study design and 197 methodology, generalizability, limitations, sensitivity analyses, and information 198 relevant to providing a balanced and complete presentation Q. A.6. Does the CARSE standard apply only to the economic components of HCEI, or 201 does it also apply to the other components? A. A.6. Under section 502(a), HCEI includes the clinical data, inputs, clinical or other 204 assumptions, methods, results, and other components underlying or comprising 205 the analysis of a drug s economic consequences. FDA considers the CARSE 206 standard in section 502(a) to apply to all components of HCEI, including inputs 207 and assumptions related to both economic consequences and clinical outcomes 208 (i.e., safety and/or effectiveness). As discussed previously in Q.A.4/A.A.4, such 209 information must also relate to an approved indication Q. A.7. What information should firms include when disseminating HCEI? A. A.7. To enable payors to make informed coverage and reimbursement decisions and to 214 help ensure that the information is not false or misleading under section 502(a), 215 firms should include appropriate background and contextual information 216 necessary to allow payors to fully understand the HCEI, including the elements 217 discussed briefly below. This information, if applicable, should be presented 218 clearly and prominently Study Design and Methodology 221 9

13 222 Firms should include an accurate overview of the design of the economic 223 analysis, including a statement of the study objectives. For example, a clear 224 description of the hypothesis tested should be provided and potential biases and/or 225 confounders should be acknowledged. In addition, the following information 226 about the study and/or methodology should be presented: Type of Analysis: The type of economic analysis selected (e.g., cost- 229 minimization analysis, cost-effective analysis, cost-utility analysis, cost- 230 benefit analysis, cost-consequence analysis) should be stated and the reason 231 for its choice should be explained Modeling: The type of modeling technique should be disclosed, with an 234 explanation of the model choice, its scope, and its key variables/parameters The rationale and consequences of including and excluding specific variables 236 in economic models should be discussed in the analysis Patient Population: Details about the patient population should be specified, 239 including the number of patients and relevant demographic information, such 240 as age, gender, ethnicity, clinical characteristics, and socioeconomic 241 status. 30, Perspective/Viewpoint: The perspective or viewpoint of the economic analysis 244 should be clearly stated so that payors can understand the rationale for the 245 selection of inputs (e.g., outcome measures, time periods, costs) and can, 246 therefore, determine whether the HCEI is relevant to their particular health 247 care organizations. Possible viewpoints can include those of the patient, 248 employer, health care provider (e.g., clinician, institution), payor, regulatory 249 body (e.g., government agency), or society (i.e., everyone impacted by the 250 treatment). 32, Drummond MF, Jefferson TO, Guidelines for Authors and Peer Reviewers of Economic Submissions to BMJ, BMJ, 1996;313:(7052): Husereau D, Drummond M, Petrou S, et al., Consolidated Health Economic Evaluation Reporting Standards (CHEERS) Explanation and Elaboration: A Report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force, Value Health, 2013;16: Gold MR, Siegel JE, Russell LB, et. al., editors, Cost-Effectiveness in Health and Medicine, New York, NY: Oxford University Press, Husereau, et al., op cit. 32 Gold, et al., op cit. 33 Drummond, et al., op. cit. 10

14 252 Treatment Comparator: The choice of comparator treatment (e.g., other 253 drugs, other medical care, no treatment) should be fully explained. 34, Time Horizon: The choice of time horizon should be clearly stated and 256 explained, including its relation to the major and relevant clinical outcomes 257 (e.g., safety and effectiveness) and economic consequences related to the 258 treatment of interest and its comparators. 36, Outcome Measures: The outcome measure(s) chosen should be fully 261 described, as should the sources of clinical and/or nonclinical data. For 262 example, clinical outcomes chosen could include PROs (e.g., 263 compliance/adherence, work productivity, basic activities of daily living) or 264 QALYs. Data sources may include clinical and nonclinical studies or other 265 sources, such as administrative databases (e.g., health plan databases), 266 electronic health records (EHRs), and registries Cost Estimates: All of the relevant resource items for measurement and 269 valuation for a treatment pathway in an economic analysis should be 270 identified. Reference should be made to the source of cost data, including the 271 date of the pricing. 38 In addition, full disclosure of and explanation for any 272 data manipulations and methods (e.g., discount rates, adjustments for 273 inflation, currency conversion) should be included Assumptions: A comprehensive listing of all assumptions (clinical and 276 nonclinical) and associated rationales should be made explicit in the 277 explanation of the methodology for the economic analysis. 40 Assumptions 278 may include, for example, information related to patient demographics or 279 characteristics, natural disease course, disease management/clinical practice, 280 and cost of clinical events. All evidence to support assumptions made should 281 be provided Gold, et al., op. cit. 35 Husereau, et al., op. cit. 36 Gold, et al., op. cit. 37 Husereau, et al., op. cit. 38 Ibid. 39 Ibid. 40 Ibid. 11

15 Generalizability Generalizability refers to the applicability of HCEI obtained in one health care 286 setting or patient population to another. Any factors which may limit the 287 generalizability of the economic analysis should be disclosed Limitations A discussion of the limitations of the economic analysis should be made 292 explicit. 42 Factors that may affect the interpretability and reliability of an 293 economic analysis include, but are not limited to, limitations of the study design, limitations of the data sources, incomplete data, assumptions made, choice of 295 comparators, and exclusion of certain clinical outcomes. For example, regarding 296 study design, limitations and methodological issues associated with observational 297 studies 44 and indirect treatment comparisons 45 should be fully described, as they 298 may inform conclusions that can be reliably made based on these analyses Sensitivity Analysis Uncertainty may arise from data sources, extrapolation, or analytical methods 303 employed in an economic analysis. Therefore, uncertainties that could affect the 304 conclusions in HCEI should be identified, and a sensitivity analysis should be 305 performed. HCEI should include adequate disclosures and rationales regarding 306 the method used for the sensitivity analysis, the variables chosen, and the ranges 307 for those variables Additional Material Information for a Balanced and Complete Presentation Siegel JE, Weinstein MC, Russell LB, et al., Recommendations for Reporting Cost-Effectiveness Analyses, Panel on Cost Effectiveness in Health and Medicine, JAMA, 1996;276(16): Gold, et al., op. cit. 43 Regarding study design limitations, firms should disclose whether the study lacked randomization, blinding, or a control group; lacked assay sensitivity; failed to include pre-specified endpoints; failed to include endpoints that are valid and reliable measures of the outcomes of interest; failed to identify dosing, patient population, patient drop outs, selection and timing of endpoints; failed to meet the primary endpoint; etc. 44 Berger ML, Martin BC, Husereau D, et al., A Questionnaire to Assess the Relevance and Credibility of Observational Studies to Inform Health Care Decision Making: An ISPOR-AMCP-NPC Good Practice Task Force Report, Value Health, 2014;17(2): Song F, Loke YK, Walsh T, et al., Methodological Problems in the Use of Indirect Comparisons for Evaluating Healthcare Interventions: Survey of Published Systemic Reviews, BMJ, 2009;338:b Husereau, et al., op. cit. 12

16 311 A balanced and complete presentation includes material information such as the 312 following: Conspicuous and Prominent Statement Describing Material Differences: 315 If HCEI includes material differences from the FDA-approved labeling, 316 including assumptions that vary in certain respects from the information 317 presented in the FDA-approved labeling, a conspicuous and prominent 318 statement describing any material differences between the health care 319 economic information and the labeling approved for the drug 47 must be 320 presented Furthermore, firms should not misleadingly represent that the clinical 323 assumptions that vary from the FDA-approved labeling have been found by 324 FDA to be safe and effective FDA-Approved Indication/FDA-Approved Labeling: HCEI should 327 include a statement regarding the FDA-approved indication of the drug and be 328 accompanied by the most current FDA-approved labeling Disclosure of Omitted Studies or Data Sources: As a general matter, the 331 presentation of HCEI would not be considered to be balanced and complete if 332 relevant data or information is available but was not considered and included 333 in the analysis. This is especially true if the omitted data or information is 334 from rigorous studies (e.g., adequate and well-controlled trials). It is, 335 therefore, recommended that firms perform a comprehensive literature search 336 and that their HCEI include an explanation of the methods used in the 337 literature search (e.g., databases or sources used, time period covered, and 338 criteria/keywords used to search the databases and sources and to determine 339 what data or information to include/exclude). If HCEI is created without 340 using all available relevant data, HCEI should clearly explain that certain 341 studies or data sources were omitted from the analysis, the reasons they were 342 not included, and how such a selective inclusion of studies or data sources 343 may change or affect the conclusions Risk Information: HCEI should disclose important risk information 346 associated with the approved use of the drug and, under section 502(a), must 347 disclose any additional risk information related to clinical assumptions in 348 economic analyses that vary from the FDA-approved labeling (e.g., risks 349 observed in a particular patient subgroup) See section 502(a). Factors that can influence the conspicuous and prominent presentation of a statement include, but are not limited to, the location of the statement; the font size and style of the statement text; the contrast between text and background; and the white space between and around text. 13

17 351 Financial/Affiliation Biases: HCEI should disclose potential financial or 352 affiliation biases, such as the disseminating firm s role in funding underlying 353 research or in drafting underlying publications or presentations or the names 354 of any authors of studies or analyses who received compensation from the 355 firm or who had a significant financial interest in the firm, to the extent 356 reasonably known by the firm at the time of dissemination Q. A.8. If HCEI is based on COAs or other health outcome measures, are there any 359 additional considerations of which firms should be aware? A. A.8. When HCEI includes COAs (e.g., PROs, including compliance/adherence, work 362 productivity, basic activities of daily living) or other measures of health outcomes 363 (e.g., QALYs), information regarding the validity and reliability of the measures 364 used in assessments of the COA (as determined by experts familiar with 365 evaluating the merits of a particular COA) 48 or the health outcome measure 366 should be included Regarding health outcome measures such as QALYs, the following should be 369 considered to facilitate interpretability and comprehensibility of the information: 370 (1) the methods by which the patient s health status is captured should be 371 disclosed, and the rationale for the health status measures included in the analysis 372 (e.g., physical function, psychological function, social function, impairment, pain) 373 should be provided and (2) the methods for the valuation of health outcomes 374 should be disclosed, and their appropriateness for the patient population and the 375 disease or condition being studied should be explained Q. A.9. Is HCEI for prescription drugs disseminated in accordance with section 502(a) 378 considered to be promotion? Do FDA s requirements for promotional 379 materials apply to HCEI? A. A.9. HCEI disseminated in accordance with section 502(a) is promotion, and, 382 therefore, is subject to FDA s requirements for submission of promotional 383 materials. These include, but are not limited to, the post-marketing requirement at CFR (b)(3)(i) to submit such materials to FDA at the time of initial 385 publication or dissemination (using Form FDA 2253 (Transmittal of 386 Advertisements and Promotional Labeling for Drugs and Biologics for Human 387 Use)) and, for HCEI about drugs submitted for approval under the accelerated 388 approval pathway or about drugs approved based on animal studies, 49 the 389 requirements regarding pre-dissemination submission of promotional materials. 48 For further guidance regarding characteristics of valid and reliable assessments of COAs, please see FDA s guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 49 See 21 CFR , , , and

18 390 All supporting information for HCEI should be referenced and be made available 391 upon request Q. A.10. What are the Agency s policies for communication of HCEI regarding 394 unapproved uses of approved drugs? A. A.10. FDA has issued a draft guidance describing our thinking on how firms can 397 respond to unsolicited requests, including requests from payors, for unapproved 398 use information related to their FDA-approved prescription drugs and FDA- 399 approved or cleared medical devices. 51 In addition, FDA has provided separate 400 guidances describing recommended practices for the dissemination by firms of 401 scientific and medical publications discussing unapproved uses of approved drugs 402 or approved or cleared medical devices. 52, Q. A.11. What are the Agency s policies regarding risk-sharing and other value-based 405 contracts between firms and payors? A. A.11. This guidance addresses the communication of HCEI to payors, which may 408 include communication of HCEI in the course of discussions between firms and 409 payors related to risk-sharing and other value-based contracts. This guidance, 410 however, is not intended to address the terms of contracts between firms and 411 payors. FDA does not regulate the terms of contracts between firms and payors B. Communications by Firms to Payors Regarding Investigational Drugs and 414 Devices Medical product firms may wish to provide certain types of information to payors regarding 417 their investigational products. Such information may help payors plan and budget for future 418 coverage and/or reimbursement decisions prior to FDA approval or clearance of 419 investigational products. This section provides answers to frequently asked questions on this 420 topic In addition, under section 502(a), if FDA requests submission of information that is relevant to the substantiation of HCEI, firms are required to provide FDA such information, which may include the primary data and analysis methods used to support the HCEI. 51 FDA s draft guidance Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices. 52 FDA s guidance Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (January 2009), available at 53 FDA s revised draft guidance Distributing Scientific and Medical Publications on Unapproved New Uses Recommended Practices (February 2014). 15

19 422 Q. B.1. What are the types of information covered by this section of the draft guidance 423 and what is FDA s approach with respect to firms that wish to provide such 424 information prior to FDA approval or clearance of an investigational product? A. B.1. FDA does not intend to object, under 21 CFR 312.7(a) or 21 CFR 812.7(a) or 427 otherwise, to the following types of information about investigational products (as 428 defined in this guidance) provided by firms to payors prior to FDA approval or 429 clearance, that is unbiased, factual, accurate, and non-misleading and when 430 presented with information discussed in Q.B.2/A.B.2: Product information (e.g., drug class, device design) Information about the indication sought, such as information from the clinical 435 study protocol(s) about endpoint(s) being studied and the patient population 436 under investigation (e.g., number of subjects enrolled, subject enrollment 437 criteria, subject demographics) Factual presentations of results from clinical or preclinical studies (i.e., no 440 characterizations or conclusions should be made regarding the safety or 441 effectiveness of the product) Anticipated timeline for possible FDA approval/clearance Product pricing information Targeting/marketing strategies (e.g., outreach activities planned to generate 448 prescriber awareness about the product) Product-related programs or services (e.g., patient support programs) Q.B.2. What other information should firms provide to payors when communicating 453 information about their investigational products? A. B.2. FDA recommends that firms provide the following information to payors when 456 communicating information about investigational products: A clear statement that the product is under investigation and that the safety or 459 effectiveness of the product has not been established Information related to the stage of product development (e.g., the phase of 462 clinical trial in which a product is being studied and how it relates to the 463 overall product development plan) FDA also suggests that firms provide follow-up information to payors if 466 previously communicated information becomes outdated as a result of significant 467 changes or as a result of new information regarding the product (e.g., failure to 16

20 468 meet primary effectiveness endpoint in the phase 3 trial) or its review status (e.g., 469 an application is determined to not be ready for approval upon completion of the 470 review cycle, a study is placed on a clinical hold) Q. B.3. What types of information would be considered inappropriate to communicate 473 to payors about investigational products? A. B.3. Communications between firms and payors that represent that an investigational 476 product is FDA-approved/cleared or otherwise safe or effective for the purpose(s) 477 for which it is under investigation would not be appropriate. 17